catalysts Article
Highly Efficient Cationic Palladium Catalyzed Acetylation of Alcohols and Carbohydrate-Derived Polyols Enoch A. Mensah *, Francisco R. Reyes and Eric S. Standiford Department of Physical Sciences, Indiana University Southeast, New Albany, IN 47150, USA;
[email protected] (F.R.R.);
[email protected] (E.S.S.) * Correspondence:
[email protected]; Tel.: +1-812-941-2305; Fax: +1-812-941-2637 Academic Editor: Kei Manabe Received: 22 December 2015; Accepted: 3 February 2016; Published: 10 February 2016
Abstract: The development of a new facile method for the acetylation of alcohols and carbohydrate-derived polyols is described. This method relies on the nature of the cationic palladium catalyst, Pd(PhCN)2 (OTf)2 which is generated in situ from Pd(PhCN)2 Cl2 and AgOTf to catalyze the acetylation reaction. This new acetylation protocol is very rapid and proceeds under mild conditions with only 1 mol% of catalyst loading at room temperature. This new method has been applied to a variety of different alcohols with different levels of steric hindrance, as well as carbohydrate-derived polyols to provide the corresponding fully acetylated products in excellent yields. Keywords: acetylation; acetic anhydride; cationic palladium (II) species; carbohydrate-derived polyols
1. Introduction Manipulation of functional groups through their protection and deprotection is of prime importance in organic synthesis, resulting in the eventual synthesis of bioactive and medicinally important natural products. Of particular importance in this endeavor is the protection of hydroxy functional groups in reaction intermediates during multistep organic synthesis [1,2]. Of the various methods used to mask hydroxy groups, acetylation of hydroxy groups to the corresponding acetate esters is the most common, due to the ease of introduction of the acetyl group as well as its removal [3,4]. The traditional and the most widely used method of acetylating alcohols involve the use of acetic anhydride or acid chlorides in the presence of amine bases such as pyridine and trimethylamine [5]. While this traditional method of acetylating alcohols proceeds well, they usually require long reaction times, and the removal of pyridine is also tedious. To circumvent these problems, several methods for the acetylation of alcohols have been reported in recent years. Some notable examples include the use of tributylphosphine [6,7], bromine [8], p-Toluenesulfonic acid [9], alumina [10], scandium triflate [11], indium triflate [12,13], bismuth triflate [14], trimethylsilyl triflate [15], copper triflate [16], cerium triflate [17], ruthenium chloride [18], sulfamic acid [19], montmorillonite K-10 [20], molecular sieves [21], iron (III)chloride [22], magnesium bromide [23], tantalum chloride [24], vanadyl acetate [25], N-bromosuccinamide (NBS) [26], 3-nitrobenzeneboronic acid [27], lithium perchlorate (LiClO4 ) [28], silica gel supported sodium hydrogen sulfate [29], sodium acetate trihydrate [1], dried sodium bicarbonate [30] and Iodine [31,32]. While these methods provides viable alternative for acetylating alcohols, some of these methods utilizes catalysts that are expensive, moisture sensitive, require long reaction times and tedious work-up protocols and sometimes result in low yields.
Catalysts 2016, 6, 27; doi:10.3390/catal6020027
www.mdpi.com/journal/catalysts
Catalysts 2016, 6, 27
2 of 10
This therefore Catalysts 2016, 6, 27calls for the development of a new and simple acetylation protocol to complement 2 of 10 the existing current methods for acetylating alcohols and polyols. therefore forreports the development of a new and simple protocol to of As a This result of the calls earlier by the Nguyen research group acetylation in employing the use complement the existing current methods for acetylating alcohols and polyols. cationic palladium (II) species to activate glycosyl trichloroacetimidates resulting in the stereoselective As a result of the earlier reports by the Nguyen research group in employing the use of cationic formation of glycosides [33,34], we hypothesized that these cationic palladium (II) species could palladium (II) species to activate glycosyl trichloroacetimidates resulting in the stereoselective equally be effective in activating acetic towards the cationic acetylation of alcohols. This prompted formation of glycosides [33,34], we anhydride hypothesized that these palladium (II) species could us to equally investigate the effectiveness of these cationic palladium (II) species as catalyst in activating be effective in activating acetic anhydride towards the acetylation of alcohols. This aceticprompted anhydride the acetylation of alcohols. palladium catalysts are in either ustowards to investigate the effectiveness of these These cationiccationic palladium (II) species as catalyst activatingavailable acetic anhydride the acetylation of alcohols. These To cationic palladium commercially or easytowards to prepare, easy to handle and stable. the best of our catalysts knowledge, arethese eithercatalysts commercially availableacetic or easy to prepare, easy to the handle and stable. To the best ourbeen the use in activating anhydride towards acetylation of alcohols hasofnot knowledge, the use these catalysts in activating acetic anhydride towards the acetylation of alcohols studied. We report herein a novel method that utilizes cationic palladium (II) species as catalyst in the has notofbeen studied. We report herein a novel method that utilizes cationic palladium (II) species as acetylation alcohols and carbohydrate-derived polyols. catalyst in the acetylation of alcohols and carbohydrate-derived polyols.
2. Results and Discussion
2. Results and Discussion
To investigate the efficiency of the cationic palladium (II) species in activating acetic anhydride, To investigate the efficiency of the cationic palladium (II) species in activating acetic anhydride, a preliminary study of this new acetylation initiatedusing usingbenzyl benzyl alcohol a model a preliminary study of this new acetylationprotocol protocol was was initiated alcohol 1 as1aas model substrate and acetic anhydride 2 as thethe acetylation 1). substrate and acetic anhydride 2 as acetylationreagent reagent (Table (Table 1). Table 1. Acetylation of benzyl alcohol catalyzed by cationic palladium (II) species.
Table 1. Acetylation of benzyl alcohol catalyzed by cationic palladium (II) species.
OH
+
(1 equiv.) 1
Entry Entry 1 21 3 42 53 6 74 a b
Catalyst Catalyst Pd(CH3 CN)4 (BF4 )2 Pd(CH33CN) CN)44(BF Pd(CH (BF44))22 Pd(PhCN)2 (OTf)2 a Pd(CH3CN)(OTf) 4(BF4)2a Pd(PhCN) 2 2 a Pd(PhCN) (OTf) 2 Pd(PhCN)2(OTf)22 a Pd(PhCN)2 (OTf)2 a a Pd(PhCN) (OTf)22 a Pd(PhCN)22(OTf)
Ac2O (2 equiv.)
Catalyst 3
2
Loading (mol %) Loading (mol %) 10 105 10 57 105 2 71
OAc
CH2Cl2 Temperature Time (min) Temperature Time (min) 25 ˝ C 30 ˝C 25 30 25°C 30 25 ˝ C 5 25 30 ˝C 25°C 5 ˝C 25 55 25 °C 25 ˝ C 5 ˝C 25°C 5 25
Yield (%) bb Yield (%) 75 75 72 95 72 93 96 95 95 95 93
Pd(PhCN)2 (OTf)2 was generated in situ from Pd(PhCN)2 Cl2 (1 equiv.) and AgOTf (2 equiv.) in CH2 Cl2 (1.25M). 5 25 °C 5 96 5 Pd(PhCN)2(OTf)2 a Isolated yield.
6
Pd(PhCN)2(OTf)2 a
2
25 °C
5
95
Upon treating the reacting partners 1 and 2 with 10 mol% of a commercially available cationic 1 25 °C 5 95 7 Pd(PhCN)2(OTf)2 a palladium (II) catalyst, tetrakis(acetonitrile)palladium (II) bis tetrafluoroborate (Pd(CH3 CN)4 (BF4 )2 ), a Pd(PhCN)2(OTf)2 was generated in situ from Pd(PhCN)2Cl2 (1 equiv.) and AgOTf (2 equiv.) in the acetylation reactionb proceeded to completion within 30 minutes, as evident by TLC (Thin layer CH2Cl2 (1.25M). Isolated yield. chromatography), affording the desired benzyl acetate 3 in good yield (Table 1, entry 1). Upon treating the reacting partners 1 and 2 with 10 mol% of a commercially available cationic This preliminary result was encouraging because it indicates that cationic palladium (II) catalyst palladium (II) catalyst, tetrakis(acetonitrile)palladium (II) bis tetrafluoroborate (Pd(CH3CN)4(BF4)2), could be employed in activating acetic anhydride towards the acetylation of alcohols. Upon reducing the acetylation reaction proceeded to completion within 30 minutes, as evident by TLC (Thin layer the catalyst loading to 5 mol%, there was no erosion of the isolated yield, and the reaction rate also chromatography), affording the desired benzyl acetate 3 in good yield (Table 1, entry 1). This remained unchanged 1, entry 2). In our quest to that further increase the catalytic activity of the preliminary result (Table was encouraging because it indicates cationic palladium (II) catalyst could be cationic palladium (II) catalyst, investigated thetheeffect of the of nature of the counter-ions employed in activating acetic we anhydride towards acetylation alcohols. Upon reducing theused. Earliercatalyst reportsloading in utilizing the nature counter-ions catalytic activity [35,36], prompted to 5 mol%, thereofwas no erosion to ofinfluence the isolated yield, and the reaction rate also us remained (Table 1, entry 2). In our quest to2further increase thefor catalytic activity ofreaction. the to design a newunchanged cationic palladium (II) species Pd(PhCN) (OTf)2 as catalyst the acetylation cationic palladium (II) catalyst, we investigated the effect of the nature of the counter-ions used. Pd(PhCN)2 (OTf)2 was generated in situ from commercially available Pd(PhCN)2 Cl2 and AgOTf [33]. reports in utilizing the nature of counter-ions to influence activity [35,36],(OTf) prompted UponEarlier treating the reacting partners 1 and 2 with 10 mol% of thecatalytic catalyst Pd(PhCN) 2 2 , to our us to design a new cationic palladium (II) species Pd(PhCN)2(OTf)2 as catalyst for the acetylation amazement, the acetylation reaction was very rapid, proceeding to completion within few minutes, reaction. Pd(PhCN)2(OTf)2 was generated in situ from commercially available Pd(PhCN)2Cl2 and and affording the benzyl acetate 3 in excellent yields (Table 1, entry 3). With these encouraging results, AgOTf [33]. Upon treating the reacting partners 1 and 2 with 10 mol% of the catalyst the acetylation reaction was repeated, each time using a progressively reduced catalyst loading up until a 1 mol% catalyst loading. In all cases, the reaction was still rapid affording the benzyl acetate 3
was still rapid affording theresults, benzyl the acetate 3 in excellent yieldswas and repeated, with virtually notime erosion of the With these encouraging acetylation reaction each using a isolated yields (Table 1,benzyl entry 4–7). catalyst loading 1 mol% which resulted in the isolated yields (Table 1,the entry 4–7). ThisThis catalyst loading 1 of mol% which resulted the was still rapid affording acetate 3initial in initial excellent yields andofwith virtually no erosion ofinthe isolated yields (Table 1, entry 4–7). This initial catalyst loading of 1 mol% which resulted in the progressively reduced catalyst loading up until a 1 mol% catalyst loading. In all cases, the reaction complete conversion of benzyl the4–7). benzyl alcohol to corresponding the corresponding benzyl acetate 3 (Table entry complete conversion alcohol 1 to 1the acetate 3 (Table 1, entry 7) 7) isolated yields (Table of 1, the entry This initial catalyst loading ofbenzyl 1 mol% which resulted in1,the complete conversion of the benzyl alcohol 13 to the corresponding benzyl acetate 3−1no (Table 1, entry 7) was still rapid affording the benzyl acetate in excellent yields and with virtually erosion of the −1 generated a2016, turnover (TON) of 100the and a turnover frequency (TOF) 1200 generated a turnover (TON) of 100 and a turnover frequency (TOF) of 1200 h . h1, .entry complete conversion thenumber benzyl alcohol 1 to corresponding benzyl acetate 3of(Table 7) Catalysts 6, of 27number 3 of 10 −1 generated athe turnover number (TON) of 100initial andofacatalyst frequency of 1200the hresulted .efficacyinofthe isolated yields (Table 1, entry 4–7). condition This loading of 1(TOF) mol% which optimum acetylation 1turnover mol% catalyst loading in hand, WithWith optimum acetylation mol% catalyst loading in hand, the of this this generated athe turnover number (TON) condition of 100 andofa 1turnover frequency (TOF) of 1200 h−1.efficacy With the optimum acetylation condition of 1 mol% catalyst loading in hand, the efficacy of complete conversion of the benzyl alcohol 1 to the corresponding benzyl acetate 3 (Table 1, entry 7)of Pd(PhCN) 2 (OTf) 2 , to our amazement, the acetylation reaction was very rapid, proceeding to Catalysts 2016, 6, 27 3 of ofthis 10 catalyst was evaluated by comparing this protocol to other reported methods of acetylation catalyst evaluatedacetylation by comparing this of protocol other loading reportedinmethods acetylation Withwas the optimum condition 1 mol%tocatalyst hand, theofefficacy of this −1 catalyst was evaluated comparing thisand protocol toacetate other methods of generated a turnover number 100 a turnover (TOF) of 1200 h acetylation . entry 3). of completion within fewby minutes, andof affording the benzyl in excellent yields (Table 1, alcohols using benzyl as model the model substrate (Table 2).3reported alcohols using benzyl alcohol as (TON) the substrate (Table 2).frequency catalyst was evaluated by alcohol comparing this protocol to other reported methods of acetylation of alcohols using benzyl alcohol as thecondition model substrate (Table 2).was With the optimum acetylation of 1 mol% catalyst loading in hand, efficacy With these encouraging results, the acetylation reaction repeated, each the time using ofa this alcohols usingTable benzyl alcohol asvirtually the model 2). with Table 2. Comparison of some acetylation benzyl alcohol substrate. 2. Comparison of some acetylation methods with benzyl alcohol as substrate. in excellent and with nosubstrate erosion of(Table isolated yields (Table entry This initial progressively reduced loading up until a the 1methods mol% catalyst loading. In1, allas cases, the reaction catalyst wasyields evaluated bycatalyst comparing this protocol to other reported methods of4–7). acetylation of Table 2. Comparison of some acetylation methods with benzyl alcohol as substrate. was still rapid affording the benzyl acetate 3 in excellent yields and with virtually no erosion of the catalyst loading of 1 mol% which resulted in the complete conversion of the benzyl alcohol 1 to the Table 2. Comparison some methods with benzyl alcohol as substrate. alcohols using benzyl alcoholofas the acetylation model substrate (Table 2). isolated yields (Table 1, entry 4–7). This initial catalyst loading of 1 mol% which (TON) resultedofin100 the and corresponding benzyl acetate 3 (Table 1, entry 7) generated a turnover number OH Catalyst Catalyst OAc OAc Table 2.OH Comparison of some acetylation methods with benzyl alcohol as substrate. + O Ac + O Ac ´ 1 complete conversion of the benzyl alcohol 1 to the corresponding benzyl acetate 3 (Table 1, entry 7) 2 h 2. OH of a turnover frequency (TOF) Catalyst OAc + 1200 Ac o frequency (TOF) of 1200 o OH +number 2O −1. Catalyst OAc generated a turnover (TON) of 100 and a turnover h 25 C Co catalyst Ac2Ocondition of 125 With the optimum acetylation mol% loading in hand, the efficacy of this With the optimum acetylation condition of 1 mol% catalyst loading in hand, the efficacy of this o25 C C reported methods of acetylation catalyst was evaluatedOH by comparing protocol25toCatalyst other OAc of alcohols + comparing Acthis catalyst was evaluated by 2O this protocol to other reported methods of acetylation of Entry Catalyst Catalyst Loading (min)Yield Yield References Entry Catalyst Loading (mol(mol %) o%)TimeTime (min) (%) (%)References using benzylCatalyst alcohol as the model substrate (Table 2). alcohols using benzyl alcoholCatalyst as the model substrate 25(Table Entry Catalyst Loading (mol %)C 2). Time (min) Yield (%) References Entry Catalyst Catalyst Loading (mol %) Time (min) Yield (%) References RuCl 5 10 alcohol 95 1 1 RuCl 5acetylation 95 [18] [18] Table 2.3 Comparison of some methods with with10 benzyl as substrate. Table 2.3 Comparison of some acetylation methods benzyl alcohol as substrate. 1 RuCl3 5 10 95 [18] Entry Catalyst Catalyst Loading (mol %) Time (min) Yield (%) References 1 RuCl3 5 10 95 [18] Cu(OTf) 2 2 2 Cu(OTf) 2 2 2 30 30 97 97 [16] [16] 2 Cu(OTf)2 OH + 30 97 [16] Catalyst OAc Ac22O 52 RuCl 2 1 Cu(OTf) 2 3 30 10 97 95 [16][18] 3 5 60 96 3 Bi(TFA) o 5 60 96 [37] [37] 3 Bi(TFA)3 25 C 5 60 96 [37] 3 Bi(TFA)3 Cu(OTf) 2 2 3 60 30 96 97 [37][16] 3 2 Entry Bi(TFA) Catalyst Catalyst5Loading Yield References 2ZrCl 2 600 93 Cp 2 1 1 (mol %) Time 600(min) 93 (%) [38] [38] 4 4 Cp2ZrCl 2 1 600 93 [38] 4 Entry Cp2ZrCl Catalyst Catalyst Loading (mol %) Time10 (min) Yield95(%) References RuCl [18] 33 [37] Bi(TFA) 2 1 55 600 60 93 96 [38] 4 3 1 Cp2ZrCl 2 (OTf) 2 1 5 95 This Pd(PhCN) 2 (OTf) 2 1 5 95 This work 5 5 2Pd(PhCN) Cu(OTf)2 2 30 97 [16] work RuCl 3 105 95 95 [18] 2(OTf) 2 155 This work 5 3 1 Pd(PhCN) Bi(TFA) 60 96 [37] ZrCl22 3 [38] Cp22(OTf) 1 1 5 600 95 93 This work 5 4 Pd(PhCN) 4
Cp2 ZrCl2
1
600
93
[38]
2 these Cu(OTf) 2 2 able 30 catalyze [16] While all these reported methods to efficiently the of benzyl While reported methods werewere to efficiently catalyze the 97 acetylation of work benzyl 5 all Pd(PhCN) 55 9595 acetylation This 2(OTf) 2 2 11able This work 5 While Pd(PhCN) 2 (OTf) all these reported methods were able to efficiently catalyze the acetylation of benzyl alcohol the benzyl acetate in excellent yields, the use of Pd(PhCN) 2(OTf) in a complete alcohol to all the benzyl acetate excellent yields, of Pd(PhCN) 2 acetylation resulted in aof complete 3in 5 the 60 2(OTf) 962 resulted [37] 3tothese Bi(TFA) While reported methods were able to use efficiently catalyze the benzyl alcohol to theinbenzyl acetate in excellent yields, the use of Pd(PhCN)2(OTf)2 resulted in a complete conversion relatively shorter time (Table 2, entry 5). conversion in relatively shorter time (Table 2, entry 5). alcohol to the benzyl acetate in excellent yields, the use of Pd(PhCN)2(OTf)2 resulted in a complete While reported were able to efficiently catalyze the acetylation of benzyl 2ZrCl 2 methods 600catalyze 93 acetylation [38]of alcohol 4 all Cp conversion in these relatively shorter time 2,1 its entry 5).efficiently While all these reported methods were able to the benzyl The efficacy ofshorter this catalyst, as(Table well as scope and limitations evaluated by subjecting The efficacy of this catalyst, as(Table well as2, its scope and limitations was was evaluated by subjecting a a conversion in relatively time entry 5). to the benzyl acetate in excellent yields, the use of Pd(PhCN) (OTf) resulted in a complete conversion The efficacy of this catalyst, as well as its scope and limitations was evaluated by subjecting a alcohol to the benzyl acetate in excellent yields, the use of 2(OTf)2 resulted in a complete 2Pd(PhCN) 2 wide variety of sterically and diverse alcohols to new this new acetylation (Table 2(OTf) 2electronically 1 alcohols 5 was 95 condition This work 5 of sterically Pd(PhCN) wide variety and electronically to this acetylation (Table 3). The efficacy of this catalyst, as well as diverse its scope and limitations evaluated bycondition subjecting a 3). in relatively timeshorter (Table 2, entry 5). diverse wide variety ofrelatively sterically and electronically to this new acetylation condition (Table 3). conversion inshorter time (Table 2, entryalcohols 5). wide variety Table of sterically and electronically diverse alcohols to this new acetylation condition (Table 3). Table Acetylation ofas alcohols with acetic anhydride catalyzed by Pd(PhCN) 2(OTf) 2. 3. of Acetylation of alcohols with acetic anhydride catalyzed by was Pd(PhCN) 2(OTf) 2. The efficacy this catalyst, as well as as its scope and limitations was evaluated by subjecting a wide The efficacy of3. this catalyst, well its scope and limitations evaluated by subjecting a Tableall3. these Acetylation of alcohols acetic catalyzed by the Pd(PhCN) 2(OTf) 2. benzyl While reported methodswith were ableanhydride to efficiently catalyze acetylation of variety of sterically and electronically diverse alcohols to this new acetylation condition (Table 3). Table 3. Acetylation of alcohols with acetic anhydride catalyzed by Pd(PhCN) 2 (OTf) 2 . wide variety of sterically and electronically diverse alcohols to this new acetylation condition (Table 3). alcohol to the benzyl acetate in excellent yields, the use of Pd(PhCN)2(OTf)2 resulted in a complete conversion shorter time (Table 2, entry 5). Tablein3. 3.relatively Acetylation of alcohols alcohols with acetic acetic anhydride catalyzed by by Pd(PhCN) Pd(PhCN)2(OTf) (OTf)2.. Table Acetylation of with anhydride catalyzed 2 The efficacy of this catalyst, as well as its scope and limitations was evaluated2by subjecting a wide variety of sterically and electronically diverse alcohols to this new acetylation condition (Table 3).
Entry Entry Entry Entry
Table 3. Acetylation of alcohols with acetic anhydride catalyzed by Pd(PhCN)2(OTf)2.
Product Time (min) Yield Product Time (min) Yield (%) b(%) b Product Time (min) Yield (%) b Product Time (min) Yield (%) b b Entry Substrate Product Time (min) Yield (%) OAcOAc OH OH Entry Substrate Product OAc Time (min) Yield (%) b OH OAc 1 1 5 5 95 95 OH 11 5 5 9595 3 3 1 5 95 OAc Entry Substrate Product Time (min) Yield (%) b 3 Catalysts 2016, 6, 27 4 of 10 1 1 OH 3 1 Catalysts 2016,1 6, 27 5 95 4 of 10 1 OAc OAc Table 3. Cont. OAc 3 OH OH OH OAc 1 Table 3. Cont. OAc OH 1 9598 10 5 OH 22 2Entry 10 10 98 98 Substrate Time (min) Yield (%) b H3COProduct H3CO 3 H3CO H3CO 2 10 98 OAc H CO 1 Entry Substrate Time 2 10 (min) Yield 98 (%) b OH 4 4 OAc H CO H3CO3 Product H3CO3 4 OAc OAc 4 OH 2 10 98 OH H3CO H3CO N O 33 10 94 OH 2 1010 94 4 2 98 H CO N O 3 10 94 5 2 3 OH 3CO 2N 4 5 O2N OAc OH OAc OH NO2 O2N 30 92 4 O2N NO2 6 N NO O 30 92 4 2 2 O2N NO2 6
5
5
Substrate Substrate Substrate Substrate
OH OH
OH OH
OAc OAc
7
7
OAc OAc
25
25
90
90
Catalysts 2016, 6, 27 Catalysts 2016, 6, 27 Entry
Table 3. Cont. Table 3. Cont.
4 of 10
Table 3. Cont. 4 of b10 Substrate Product Time (min) Yield (%) Table 3. Cont. Entry Substrate Product Time (min) Yield (%) b Table 3.3.Cont. Table Cont. Table 3. Cont. b Entry Substrate Product (min) Yield (%) OAc Time Entry Substrate Product Time (min) Yield (%) bb b bb Table 3.Product Cont. Entry Substrate Product Time (min) Yield (%) Entry Substrate Product Time (min) Yield (%) OAc Entry Substrate Time (min) Yield (%) Table 3. Product Cont. b Entry Substrate Time (min) Yield (%) OAc bb b OAc OH Entry Substrate Product Time (min) (%) Entry Substrate Product Time (min) Yield (%) Entry Substrate Product Time (min)Yield Yield (%) OAc OAc OAc OH OAc N O Entry Substrate Product Time (min) Yield (%) 3 10 94 b Entry SubstrateOH OH O2N 2Product OAc OAc OAc Time 3 10 (min) Yield 94 (%) b 4 of 10 OH OH OH Catalysts 2016, 6, 27 5 OAc OO OH 3 3 33 1010 10 9494 94 ON N O2N 2NN 94 OAc 25 22O O2N 2 OH 1010 OH OH 2N N OO 33 10 9494 2 5 5 O N OH OO O2N N N2N 5 5 5 33 3 2 O 101010 949494 O 2N 2O OH 2 22N 5 OAc OAc 2N OO N N O Table 3. Cont. 3 10 2 2 OH 55 5 O2N 3 10 94 94 OO N2N OH 2N 2O OAc OAc 5 OAc OAc OAc OH OH O2O N2N Substrate OAc OH N5 NO2 Time (min)30 O2Product OH 92b 4 OH Yield NOOAc OAc 30 92 (%) 4 Entry OH O2N NO2 O2N 2 OAc 6 NOOAc NOOH OH OO 3030 30 9292 92 4 4 44 O2N 2OH NO O2N 92 6N 2NO 2NN NO OAc N NO O 2 22 2 22 22O 3030 OO NO OH 2 O N NO 2NO 2 N NO O 30 9292 44 6 N NO N NO OH 6 2 2 O NO 22 22 2N 22 2 22 6 6 OO N2N 6 6 NO NO NO 303030 929292 44 4 O2N NO2 22 2 2N 2O OAc NO 4 30 92 OO NO N2N NO NO N O OH 2N 22 2 30 4 2O OAc 6 6 6 2 2 NO2 O2N 30 92 92 4 OH NO2 OAc 6 O2O N2N OH NO OAc OAc OAc 6 OAc OH 2 OH OH OH OAc 5 25 90 OH 5 25 90 OAc OAc OAc OH OH OH 5 5 55 25 90 OAc 25 90 252525 909090 OH OAc 7 OH 555 25 90 7 25 25 90 55 5 909090 2525 77 77 OH OAc 7 5 25 OH 5 25 90 90 OAc7 7 7 7 OH OAc OH OAc OH OH OAc OH OAc 7OAc OH 7OAc 30 86 6 OH OH OH OAc OAc OAc 30 86 6 OH OAc 3030 30 8686 86 66 66 OH OAc 30 86 30 3030 86 8686 666 8 8 303030 868686 66 6 88 88 30 6 30 86 86 6 8 8 OAc OH OAc OH 8OAc 8 8 OAc OAc OAc OH OAc OH OH OH 10 95 7 OH 8 8OAc OH 10 95 7 OAc OAc OAc OH OH OH 95 77 777 10 95 OAc 1010 95 101010 959595 OAc OH 9 10 95 77 OH 9 101010 959595 77 7 9OAc 9 OH 10 7 OAc 9 9 10 95 95 7 OH 99 OAc OAc OH OAc OAc 99 9 OH OAc OH OH OH OAc 8 6 93 OH 8 6 93 OAc OAc OAc 9 9 OH OH OH OAc 88 888 93 OAc 93 OH 6 66 6 66 93 OAc 93 93 OH OAc OH OH 88 6 9393 10 OAc OAc 10 OH OAc OAc 88 8 66 6 939393 OH OAc OH OH OH 1010 OAc 10 8 6 OH 10 OAc OAc 8 6 93 93 OAc OH OH OH OH 1010 OAc OAc OH 1010 10 OH OAc OAc OAc OH OH OAc OAc OH 10 OAc OH OH OH 10 OAc 92 9 5 OH 92 9 5 OAc OAc OAc OH OH OH 9 5 92 OAc OAc 9292 92 99 99 55 55 OH OH 9292 5 OAc 11 OAc OH OAc 92 99 5 OH OAc OAc OH 11 OAc OH OH OH 929292 99 9 55 5 OAc OH 11 11 OAc 11 OAc 11 OAc 92 9 5 11 OH OH OH 92 9 5 11 OAc OH OAc 11 11 OAc 11 OH OAc OH 11 11 OAc OH OAc OAc OAc OAc OH OAc 10 82 10 OH 10 10 OH OH 10 82 82 10 OH OAc OAc OAc OH 1010 10 8282 82 1010 10 10 82 10 OAc OH OH OH OAc 1010 8282 1010 12 OH OH 12 101010 828282 101010 1212 12 10 10 12 10 82 82 10 1212 121212 12 12
H3C
H3
14
CH3
Catalysts 2016, 2727 Catalysts 2016, 27 Catalysts 2016, 6, Catalysts 2016, 6, 276,6,6, Catalysts 2016, 27
H AcO
H
5of of510 10 of 10 5 of 510 5 of 10
Table 3. Cont. Table 3. Cont. 92 Table 3. Cont. Table 3. Cont.
H
Table 3. Cont.
Entry Entry 15 Entry Entry Entry Entry
Substrate Substrate Substrate Substrate Substrate Substrate
11 1111 11 1111
Product Product Product Product Product Product
b b Time (min) Yield (%) b (%) Time (min) Yield Time (min) Yield (%) Time (min) Yield b b b (%) Yield TimeTime (min)(min) Yield (%)(%)
OAc OAc OAc OAc OAc OAc OAc OAc OAc OAc
OH OHOH OH OH OH OH OH OH OH
1313 13 1313 H3H C 3CC OH H3H C 3CC OAc H3C H3C OAc OH H3H C3 O OAc H3H C3 O OHOOOH OAc OH O O OOOOAc O O H C H3H C 3CC O OOO 3HH O OOOO H3C H H3C 3CC H3H C3 3C3 O O O O O O 12 OO O OO O 12 12 1212 12 OOO OOO OO O OO O O O O OO O H3H CH H3H CH C CC H C H3C C 3 3 3 H3C3CH H3C3CH CH CH 3CH CH 3CH CH3 CH 3 3 14143 CH 14 1414 3 3 3 3
1515 15 1515 15
99 9999 99 99 99
10 10 10 10 1010
78 7878 78 78 78
9
13
13 13 1313
92
9292 H HHHHHHHH 9 9 99 92 9292 H H AcO AcO AcO AcO H H AcO HO 13 H HHH HHH H H H15 15 H 15 1515 HO HOHO HO H H a Pd(PhCN)H 2 (OTf)H 2 was generated in situ from Pd(PhCN)2 Cl2 (1 equiv.) and AgOTf (2 equiv.) in CH2 Cl2 (1.25M). b
Isolated yield.
a Pd(PhCN) Pd(PhCN) 2(OTf)2 was generated in situ from Pd(PhCN) 2Cl2Cl (12 equiv.) AgOTf (2 equiv.) 2 was generated in situ from Pd(PhCN) (1 equiv.) and AgOTf (2 equiv.) Pd(PhCN) 2(OTf)22(OTf) was generated in situ from Pd(PhCN) 2Cl2 (1 2equiv.) andand AgOTf (2 equiv.) in in in a Pd(PhCN) 2(OTf)2 was generated in situ from Pd(PhCN)2Cl2 (1 equiv.) and AgOTf (2 equiv.) in b b Isolated 2Cl (1.25M). Isolated yield. bthe 22Cl 2 (1.25M). yield. CH In all cases, acetylation reaction proceeded smoothly and rapidly affording the corresponding 2Cl 2 (1.25M). Isolated yield. CHCH 2Cl2 (1.25M). b Isolated yield. CH
a
a
acetates in all excellent yields. Particularly interesting is thesmoothly acetylation of highly deactivated alcohols all cases, reaction proceeded smoothly and affording cases, theacetylation acetylation reaction proceeded smoothly andrapidly rapidly affording the In In all thethe acetylation reaction proceeded and rapidly affording thethe InIn cases, all cases, the acetylation reaction proceeded smoothly and rapidly affording the such as 4-nitrophenol and 2,4-dinitrophenol, which were completely acetylated at short reaction times corresponding acetates in excellent yields. Particularly interesting is the acetylation of highly corresponding acetates excellent yields. Particularly interesting the acetylation acetylation highly corresponding acetates in excellent yields. Particularly interesting is the of highly corresponding acetates ininacetate excellent yields. Particularly interesting isisacetylation the ofof highly affording the corresponding 5 and 6 in excellent yields (Table 3, entry 3–4). deactivated alcohols such as 4-nitrophenol and 2,4-dinitrophenol, which were completely acetylated deactivated alcohols such as4-nitrophenol 4-nitrophenol and2,4-dinitrophenol, 2,4-dinitrophenol, which werecompletely completely acetylated deactivated such as 4-nitrophenol and 2,4-dinitrophenol, which werewere completely acetylated deactivated alcohols such as and which acetylated Thealcohols efficacy of this cationic palladium (II) catalyst was again evaluated using highly hindered at short reaction times affording the corresponding acetate 5 and 6 in excellent yields (Table 3, entry short reaction times affording thecorresponding corresponding acetate 56and and 6ininacetylation excellent yields (Table entry at short reaction times affording the acetate 5both and5cases, in excellent yields (Table 3,proceeded entry such as adamantanol andcorresponding diphenylmethanol. In reaction atatshort reaction times affording the acetate 6the excellent yields (Table 3,3,entry 1 alcohols –4). 3well affording the acetylated products 7 and 8 in excellent yields (Table 3, entry 5 –6). 4). 3–4). 33––4). The efficacy of of thisthis palladium (II) catalyst was again evaluated using highly acetylation ofcationic monosaccharides usually the first step towards the synthesis ofhindered complex The efficacy cationic palladium (II) catalyst was again evaluated using highly hindered The Since efficacy of this palladium (II)is catalyst was again evaluated using highly hindered The efficacy of cationic this cationic palladium (II) catalyst was again evaluated using highly hindered alcohols such as adamantanol and diphenylmethanol. In both cases, the acetylation reaction carbohydrates [12], the efficacy of this cationic palladium (II)both catalyst Pd(PhCN) in the alcohols such as adamantanol and diphenylmethanol. In cases, the acetylation 2 (OTf) 2 reaction alcohols such as adamantanol and diphenylmethanol. In both cases, the acetylation reaction alcohols such as adamantanol and diphenylmethanol. In both cases, the acetylation reaction proceeded well affording the acetylated products 7 and 8 in excellent yields (Table 3, entry 5 – 6). acetylation of carbohydrate-derived polyol was also investigated (Table 4). proceeded well affording the acetylated products 7 and 8 in excellent yields (Table 3, entry 5 6). proceeded well well affording the acetylated products 7 and7 8and in excellent yields (Table 3, entry 5 – 6).5 ––6). proceeded affording the acetylated products 8 in excellent yields (Table 3, entry Since acetylation of monosaccharides is usually the first step towards the synthesis of complex In this acetylation, two equivalent of acetic anhydride was used for every hydroxy group. Since acetylation monosaccharides usually thestep firststep steptowards towards thesynthesis synthesis complex SinceSince acetylation of monosaccharides is usually the first towards the synthesis of complex acetylation ofofmonosaccharides isisusually the first the ofofcomplex carbohydrates the efficacy of this cationic palladium (II) catalyst 2yields (OTf) 2(Table in thethe Incarbohydrates all cases, [12], the[12], acetylation reaction afforded the acetylated sugars 16–22 inPd(PhCN) excellent 4, [12], the efficacy of this cationic palladium (II) catalyst Pd(PhCN) 22(OTf) carbohydrates the efficacy of this cationic palladium (II) catalyst Pd(PhCN) 2(OTf) in the carbohydrates [12], the efficacy of this cationic palladium (II) catalyst Pd(PhCN)2(OTf)2 2inin the acetylation of carbohydrate-derived polyol was also investigated (Table 4). entry 1–7). acetylation of carbohydrate-derived polyol was also investigated (Table 4). acetylation of carbohydrate-derived polyol was also (Table 4). 4). acetylation of carbohydrate-derived polyol was investigated also investigated (Table InTothis acetylation, equivalent of acetic anhydride was used for every hydroxy group. In all determine thetwo scope and oflimits of this newwas acetylation reaction, the tolerance of theall In this acetylation, two equivalent of acetic anhydride was used for every hydroxy group. In this acetylation, two equivalent acetic anhydride used for hydroxy group. In all In this acetylation, two equivalent of acetic anhydride was usedevery for every hydroxy group. InInall cases, the acetylation reaction afforded the acetylated sugars 16–22 in excellent yields (Table Pd(PhCN) (OTf) catalyzed acetylation with several acid sensitive hydroxy protecting groups were cases, the acetylation reaction afforded the acetylated sugars 16–22 in excellent yields (Table 2 2 cases,cases, the acetylation reaction afforded the acetylated sugars 16–2216–22 in excellent yields (Table 4, 4,4,4, the acetylation reaction afforded the acetylated sugars in excellent yields (Table entry 1–7). also investigated. While the acetonide group, TBDPS and PMP (p-methoxyphenyl) protecting groups entry 1–7). entryentry 1–7).1–7). H H determine the scope and limits of this new acetylation reaction, the tolerance of of thethe were stable under the present acetylation protocol, affording the corresponding acetylated products To determine the scope and limits of this new acetylation reaction, the tolerance To To determine the scope and limits of this new acetylation reaction, the tolerance of HO To determine the scope and limits of this new acetylation reaction, the tolerancethe of the H Pd(PhCN) 2 (OTf) 2 catalyzed acetylation with several acid sensitive hydroxy protecting groups were in excellent yields (Table 3, entry 12; Table 4 entry 6–7), TMS and TBS groups were unstable Pd(PhCN) 2 (OTf) 2 catalyzed acetylation with several acid sensitive hydroxy protecting groups were Pd(PhCN) 2(OTf)2 catalyzed acetylation with several acid sensitive hydroxy protecting groups were and Pd(PhCN) 2(OTf)2 catalyzed acetylation with several acid sensitive hydroxy protecting groups were also investigated. While the acetonide group, TBDPS and PMP (p-methoxyphenyl) protecting subsequently hydrolyzed, and the resulting hydroxy group acetylated. It was also noted that also investigated. investigated. While the acetonide acetonide group, TBDPS and PMP PMP (p-methoxyphenyl) protecting also also investigated. While the acetonide group, TBDPS and and PMP (p-methoxyphenyl) protecting While the group, TBDPS (p-methoxyphenyl) protecting groups were stable under the present acetylation protocol, affording the corresponding acetylated there was a gradual loss of the acetonide group when the acetylation reaction was carried out for groups were stable under the present acetylation protocol, affording the corresponding acetylated groups were stable under the present acetylation protocol, affording the corresponding acetylated groups were stable under the present acetylation protocol, affording the corresponding acetylated products in excellent yields (Table 3, entry 12; Table 4 entry 6–7), TMS and TBS groups were unstable an extended period. products in excellent yields (Table 3, entry 12; Table 4 entry 6–7), TMS and TBS groups were unstable products in excellent yields (Table 3, entry 12; Table 4 entry 6–7),6–7), TMSTMS and TBS werewere unstable products in excellent yields (Table 3, entry 12; Table 4 entry and groups TBS groups unstable and subsequently hydrolyzed, and the resulting hydroxy group acetylated. It was also noted andsubsequently subsequently hydrolyzed, andresulting theresulting resulting hydroxy group acetylated. wasalso alsonoted noted that and subsequently hydrolyzed, and the hydroxy group acetylated. It was also noted thatthat and hydrolyzed, and the hydroxy group acetylated. ItItwas that there was a gradual loss of the acetonide group when the acetylation reaction was carried out for an there was a gradual loss of the acetonide group when the acetylation reaction was carried out for an therethere was awas gradual loss of theofacetonide group whenwhen the acetylation reaction was carried out for a gradual loss the acetonide group the acetylation reaction was carried outan for an extended period. extended period. extended period. extended period.
1
Catalysts 2016, 6, 27Table Table 4. (PhCN) (PhCN) Pd(OTf) catalyzed acetylation of carbohydrate-derived carbohydrate-derived polyols. 2Pd(OTf) 2 catalyzed acetylation of carbohydrate-derived polyols. 4. 22Pd(OTf) 22 catalyzed acetylation of polyols. Catalysts 2016, 6,Table 27 4. (PhCN) Table 4. (PhCN)2Pd(OTf)2 catalyzed acetylation of carbohydrate-derived polyols. Catalysts 2016,2016, 6, 276, 27 Catalysts
6 of 10 6 of 10 6 of 610of 10
mol% 4. (PhCN)2Pd(OTf)2 catalyzed acetylation of carbohydrate-derived polyols. 1 mol% 11 mol% Catalysts 2016, 6, 27TableTable 4. (PhCN)2Pd(OTf)2 catalyzed 1 acetylation of carbohydrate-derived polyols. 6 of 10 mol% Catalysts 2016, 6, 27 6 of 10 b bb Pd(PhCN) (OTf) Pd(PhCN) (OTf) Table 4. (PhCN) 2Pd(OTf) 2 catalyzed acetylation of carbohydrate-derived polyols. Pd(PhCN) (OTf) Table 4. (PhCN) 2Pd(OTf) 2 catalyzed acetylation of carbohydrate-derived polyols. O 2 2 b O O 2 2 2 2 O + ++ Ac Ac Pd(PhCN) (OTf) O O a Oaa Catalysts 2016, 6,2016, 27 6, 27 610of 106 of 10 Catalysts 1 mol% O 2 2 (AcO) (AcO) O Catalysts 2016, 6, 27 6 of (AcO) O Ac O a 22 (HO) n nn 1, rt, mol% (HO) Table (PhCN)+2Pd(OTf) acetylation of carbohydrate-derived (HO) Ac222Ocatalyzed n 5min 1hb (AcO)npolyols. Cl CH Catalysts 2016, 6, 27 nn 4.Table 6 of 10610of 10 , mol% rt, 5min - b1h Cl2acetylation CH (HO) rt, 5min -- 1h CH 2Cl Catalysts 2016, 4. (PhCN)2Pd(OTf) 2 catalyzed carbohydrate-derived Pd(PhCN) (OTf) 2Cl Catalysts 2016, 6 of n6, 276, 27 221,5min 1 Opolyols. 2mol% 21h , rt, -of CH
2 2 Pd(PhCN) O4. (PhCN) a O 2(OTf) 2b (AcO) + (PhCN) 2Pd(OTf) 2 catalyzed acetylation of(OTf) carbohydrate-derived O4. a 2 catalyzed Pd(OTf) acetylation of bcarbohydrate-derived polyols. n polyols. +Ac22O (HO)n TableTable Pd(PhCN) Pd(PhCN) (OTf) (AcO) O Ac 1 mol% O (%) 2 2 Product O (%) 2 2 2 n Yield c Product , rt, 5min 1h Cl CH (HO) cc Entry Substrate (%) Product Entry Substrate Yield O a O a 2 2 Table 4. (PhCN) 2 Pd(OTf) 2 catalyzed acetylation of carbohydrate-derived polyols. 1 mol% n Entry Substrate Yield Table 4.Table (PhCN) catalyzed acetylation carbohydrate-derived polyols. ,Product rt, - 1h (AcO) CH 4.Substrate (PhCN) 2Pd(OTf) acetylation of polyols. c O Ac b carbohydrate-derived (AcO) O2 catalyzed 2+Pd(OTf) 22Ac Table 4. (PhCN) 2+Pd(OTf) 22catalyzed acetylation of 5min carbohydrate-derived polyols. 2(OTf) 2Clof Entry (%) n Yield n Pd(PhCN) (HO) (HO) b O 2 -(OTf) n n 122,Cl mol% rt,22,15min 1h- 1h CHCH OAc rt, 5min mol% OAc O a 2ClPd(PhCN) OH +O 2 OAc 2 (AcO) OH Ac OH Product OAc a b 2O n(AcO) Entry Substrate Yield (%)Oc (%) c (HO) + b 1 mol% OH O Ac Product Pd(PhCN) (OTf) n Entry Pd(PhCN) (OTf) 1 mol% Yield , rt, 5min Cl CH 2 n O 1 mol% 2 - 1h 2 (HO)n O O Substrate Oc 2 2 2 2 a O b (AcO)(AcO) b O ,Product rt,OAc 5min Cl CH O + Substrate c Product +Ac O AcO 2AcO b - 1h Entry Substrate Yield (%)(%) O2OO Oa Pd(PhCN) Ac Entry Yield AcO HO n Pd(PhCN) (OTf) HO OH O 22(OTf) 2OOAc (HO) 2 n Pd(PhCN) (OTf) HO (HO) OAc O 2 2 OAc n1 O O O 2rt, 5min 2 - 1hOAc a AcO n O , rt, 5min 1h Cl CH OH AcO + HO 94 , Cl CH O AcO a 1 94 (AcO) O Ac 2 2 a AcO 1 94 HO OAc (AcO) c 2 2 Product + + Ac HO (AcO) 2 Ac n Yield (HO) OAc HO Entry Substrate OAc 2OOHCH Cl ,AcO 1 (HO) 94 nEntry 2OOH n n (%) OH OH (HO) O OAc 5min -Product 1h HO OAc Substrate Yield (%) c n n OAc OH CH , 5min rt, 5min -O 1h Cl OHO 2 2rt, 2 CH HO AcO , rt, 1h Cl HO HO 2 2 OAc OH O OAc AcO OAc Product HO HO 16OAc 16Product AcO Entry Substrate Yield (%) c (%) c 1 Entry 94Yield OH 16 Substrate O O OAc HOHO AcO OOH 1 94 16OAc AcO O AcO c HO HOSubstrate c Product Entry Product Yield (%) OH OAc OAc Entry Substrate Yield (%) c Product c Product HO Substrate Yield OAc AcO OAc 1Entry 94(%) Entry Substrate Yield 1 94(%) OAc OH AcOAcO O OH HO HO HO OH O 16 HO O OAc OAc OAc OAc OAc OH OHOH O 16OAc OH OH OAc HO HO OH AcO AcOOAc OAc 1 94 OAc OH HO HOOH OH AcO 1 94 16O16 O OAc O OHO AcO AcO HO HO HO OAc O OAc O HO OAc O O O OAc OAc AcO O OH AcO AcO 1 94 HO O AcO O AcO HO 1 94 OH O AcO O HO O HO HO 16 OAc HO HOO O O AcO AcO AcO HO AcO HO AcO 95 OAc 94 16OAc OAc AcO OH OH 95 HO HOOH AcO OAc OAc 1 21 221 1 HO 94 HOHO 95 AcO OAc OAc 94 HO HO AcO AcO AcO 94 OHOH 2 95 O AcO HO HOOH AcO OHO 16 HO OAc AcO HO 16 OCH OOCH HO HO HO OCH OAc OH OAc OCH AcO OH OOCH 3 33 OCH AcO HO OAc HO 3 HO HO 3 OCH AcO 3 OH 16 2 95 95 OCH OOAc O 3 HOHO 17 17 AcO O 3 AcO AcO 2 HO HO OOH 17161716 AcO OCH OAc AcO AcO AcO OAc O 2 2 HO HOHOHO 95 95 3 OH HO OHOCH O OCH AcO OOCH3 17 AcO AcO O3 3 OAc AcO HO HO OAc HO OH AcO OCH OCH OAc 2 95 OH HO HOOH 3 OCH 3 OCH OH O17 OAcO OH OAc AcO OAc AcO OOH 2 95 AcOAcO O3 3 HO AcO AcO HOHO AcO 17 17 HO OAc OH HO AcO OCH HO 2 95 O AcO AcO 3 OCH OCH AcO O O 2 95 HO AcO O HO 2 HO 95 3 O OCH AcO OO 3 AcO O O 17AcO OAcO HOHOHO O O 3 OAc OH AcO AcO 22 2 95 HO HO 17 AcO O HO OCH O HO AcO OAc 95 OCH OH HO 95 82 3 AcO HO HO OCHOCH 3 AcO HO AcO 3 HO 3 3 82 AcO AcO 3 HO AcO HO 17 OAc OAc AcO OH OCH OH 17 OAc AcO OH HO HOOH 3 3 82 82 OAc AcO AcO HOHO OCH HO 3 OAc O AcO OH OCH OOCH HO AcO HO 3 OCH 3 AcO 3 OCH OAc OH3 3 O O 17AcO HOHO 17 17 AcO OAc AcO HO OH 3 82 82 18OAc O 18 O OOH O 18 AcO HO 3 AcO HO OAc OH 18 AcO HO OAc OH OAc AcO OH AcO HO 3 3 82 82 HOHO OAc OH O AcO AcO O HO HO AcO OAc OAc 82 O OHOH O 18 AcO AcO OAc HO HO 3 HOHO OH AcO OAc OH AcO 18 OAc 3 82 OH OAc AcO HO OHOH OAc AcO HO OOAc O AcO O HO 3 82 OH AcO OH OAc AcO HO O 18 HO 18OAc AcO AcO HO OAc OH OH AcO O AcO O HO O HO AcO HO 3 82 82 O O AcO O HO OOOO 3 O O AcO HO AcO HO AcO18AcO OAc HOHO O AcO OAc OAc O OH OH 90 AcO AcO HO HO 3 43 443 8290 OAc AcO 18 HO OHHO AcO AcO AcO HO HO 82 AcO AcO HO 82 90 OH OH 90 4 OAc AcO OH AcO HO HOHO OAc AcO OAc OAc HO OAc O OH OH O AcO 18 OH HO AcO 18 OH HO AcO OHOH HO OAc O AcO OAc O AcO 19 HO HO 19 OAc OH 19OAc AcO19 90 90 4 AcO 1818 HOHOOH O O OAc O18OAc O 4 AcO HO AcO AcO HOHO AcO HO 4 90 OH 90 90 4 4 AcO HOO AcO OAc AcO HOHO OH 19 O OAc AcO HOHO 19 OOAc OOAc OH O OH O AcO O OH AcO OH AcO 90 4 O HO HO O AcO O OAc AcO AcO OAc AcO 19 HO AcO AcO 19 O OAc AcO 90 4 OAc O OAc O OHO O AcO O AcO HOOH AcO AcO HO AcO AcO AcO OH HO AcO AcO AcO HO AcO AcO OHOHOH OAc HO AcO OAc OAc 90 45 55 4 AcO OAc 86 O 90 86 19 O AcO OH AcO OH HO 86 HO AcO O HO OAc AcO OOAc OAc HO O O OAc AcO OH AcO O 19 86 O HOHO AcO AcO HO O OAc HOHO 90 454 4 AcO OAc OH AcO 90 AcO HO OH 20 90 AcO 20 AcO HO O O OAc AcO 20 AcO HO 19 20 OAc O19 OOAc AcO 5 AcO AcO AcO OH 5 86 86 AcO AcO OH OAc 86 OH OAc 5 OAc 1919 AcO AcOHO HOOHOH OAc O AcO OAc 19 AcO OAc O OAc OAc AcO OHOH AcO 20 OAc O 5 5 86 86 HOO 20OAc OAc AcO OAc AcO AcO HO AcO OAc O OHO OAc AcO AcO O AcO OH 5 86 O 20 AcO AcO 20 AcO AcO OAc O HO HO OAc AcO HO HO AcOAcOOAc OH 5 86 O O O OHO AcO HO OO AcO OAc AcOOH O AcO AcO AcO AcO O AcO OAc O AcO O 20 AcO HO OAc HO AcO OH AcO 56 66 5 86 HO OAc 82 AcO OH AcO 86 O 82 AcO HO 82 20 AcO AcO AcO HO OH AcO HO 6 AcO OAc OAc OAc 82 AcO HO AcO HO 82 HO AcO AcO OAc OH AcO AcO OH 565 5 86 OAc O HO OH HO HOHO 86 20 OH 86 OAc OAc 20 OAc OPMP AcO HO O OHOPMP 21OPMP OOPMP HO AcO OAc AcO21 OAc 21 HO AcO OOPMP HOHO OHOPMP 82 82 6 21 AcO 20 OOPMP O 20 6 HOHOOH OOPMP 20 OAc AcO AcO AcO O AcO HO HO HO OAc HO 82 82 6 6 AcO OPMP OH AcO AcO 21OTBDPS OTBDPS O OTBDPS HOO OTBDPS HOHO OPMP OTBDPS 21 OAc OAc OOPMP OTBDPS OPMP AcO HOHO AcO OHOTBDPS OTBDPS AcO AcO O OH 82 6 OPMP AcO 21 21OPMP HO OPMP OAc HO HO 82 6 O OPMP OO AcO O OAc AcO OH O OAc AcO OO OOOH OTBDPS AcO AcO AcO HO HO AcO HO O AcO OH OTBDPS HO O HO OPMP HO OTBDPS 85 21 HO 82 67 77 67 O O 85 AcO 82 AcO 85 OTBDPS HO AcO AcO O 85 AcO OPMP AcO OPMP O O O O OPMP AcO OTBDPS 21 HO HO AcO HO HOOTBDPS 85 AcO HO HO OTBDPS AcO HO 82 676 6 OTBDPS HO O AcO AcO HO AcO 82 AcO 82 OPMP AcO O HO AcO OPMP OCH 21 21 AcO HO HOHO HO OOCH OCH HOHO AcO OCH 3 33 OPMP HO OOCH AcO OCH OPMP HO OTBDPS 7 85 85 OCH 3 33 AcO OTBDPS 22 OPMP 3 O O OPMP OCH 2122 7 HO OTBDPS 22 AcO OPMP 3 21 O O AcO AcO OTBDPS OPMP 21 HO HO 22 HO OPMP AcO OPMP 722 equiv. 85 generated 7 of acetic 85 HO b OTBDPS OCH OTBDPS AcO a 2a equiv. bAcO bb Pd(PhCN) equiv. ofanhydride acetic anhydride were used per hydroxy group. (OTf) 2 was was generated in O AcO 2 aaequiv. anhydride were used perper hydroxy group. Pd(PhCN) 2(OTf) 2 was generated in in 3Pd(PhCN) OTBDPS OCH of acetic anhydride were used hydroxy group. 22(OTf) 2in HO HO of acetic were per group. Pd(PhCN) (OTf) generated situ from HO OTBDPS 2 was O used AcO a 2 equiv. b 2Pd(PhCN) 3 hydroxy HO 3 2(OTf)2 was generated in OOCH OCH of acetic anhydride were used per hydroxy group. AcO c22 AcO OTBDPS O 3 AcO c HO 7 85 c Pd(PhCN) Cl (1 equiv.) and AgOTf (2 equiv.) in CH Cl (1.25M). Isolated yield. OTBDPS HO HO c Isolated Cl (1 equiv.) equiv.) and AgOTf (2 equiv.) equiv.) inO22 CH Cl (1.25M). Isolated yield. situ from Pd(PhCN) OTBDPS AcO OCH 2 2Pd(PhCN) 2 (2 2 equiv.) Cl222Cl (1 and AgOTf in OTBDPS CH 2OCH Cl222Cl (1.25M). yield. situsitu from 22equiv.) (1 and AgOTf (2 in CH 223(1.25M). yield. from Pd(PhCN) OTBDPS 3 c Isolated HO22Cl OTBDPS OCH 7ofPd(PhCN) 85 O AcO asitu b2Cl 3 hydroxy 2HO (1 equiv.) and (2AcO equiv.) in22 CH 2 (1.25M). Isolated from O OCH O 3AgOTf 2 equiv. aceticHO anhydride were used per group. 2(OTf) 2 wasyield. generated in AcO 22Pd(PhCN) AcO HO a 2 equiv. b Pd(PhCN) HO OCH of acetic anhydride were used per hydroxy group. 2 (OTf) 2 was generated in 7 85 O AcO 7 85evaluated AcO 3 OCH AcO O O AcO With these exciting results, the substrate scope of Pd(PhCN) 2 (OTf) 2 was further by HO O HO HO these exciting results, theand scope ofgroup. Pd(PhCN) 2(OTf) was further evaluated by by 3substrate aWith b 2Pd(PhCN) O aequiv. b OCH With these exciting results, the substrate scope ofCH Pd(PhCN) 2(OTf) 22(OTf) was evaluated AcO 2Cl 2anhydride (1HO equiv.) AgOTf (2 equiv.) in 2Cl (1.25M). Isolated yield. situ from Pd(PhCN) O 3c222(OTf) HO AcO OCH 22 2 of acetic anhydride were used per hydroxy was generated in 2 equiv. of acetic were used per hydroxy group. Pd(PhCN) 2further was generated in HO c 2further 7 85 3 With these exciting results, the substrate scope of Pd(PhCN) 2 (OTf) was evaluated by AcO 2 Cl 2 (1 equiv.) and AgOTf (2 equiv.) in CH 2 Cl 2 (1.25M). Isolated yield. situ from Pd(PhCN) AcO With these exciting results, the substrate scope of Pd(PhCN) (OTf) was further evaluated by AcO 7 85 22 2 2 7 85 HO AcO OCH HO HO AcOpolyols OCH extending itPd(PhCN) to the the acetylation of disaccharide-derived polyols Scheme 1).c Isolated 32 (1.25M). extending itof toit the acetylation of disaccharide-derived ( Scheme 1). HO OCH 3 c Isolated HO to acetylation of disaccharide-derived polyols ((ClScheme 1). a extending binPd(PhCN) OCH 2Cl2 2(1 equiv.) and AgOTf (2 equiv.) in CH 2CH Cl 2 2(1.25M). yield. from 2were (1the equiv.) (2 equiv.) yield. in Pd(PhCN) 3 and 2situ equiv. acetic anhydride used per hydroxy group. 2 was generated AcO 3AgOTf extending it2 from to the acetylation of disaccharide-derived polyols (22 Scheme 1). 22 AcO ato HO With these exciting results, scope of Pd(PhCN) 2b(OTf) 2 was2(OTf) further evaluated by extending itsitu the acetylation ofCl disaccharide-derived polyols (Scheme 1).22(OTf) AcO OCH equiv. ofexciting acetic anhydride were used per hydroxy group. Pd(PhCN) was generated in by HOsubstrate OCH 3 HO OCH OCH With these results, the substrate scope of Pd(PhCN) (OTf) 2 was 2further evaluated 3 OCH 3 c Isolated 3 OCH 3 2 Cl 2 (1 equiv.) and AgOTf (2 equiv.) in CH 2 Cl 2 (1.25M). yield. situ from Pd(PhCN) 22 a 2 equiv. b Pd(PhCN) 3 ait 2 b 22 c of acetic anhydride were used per hydroxy group. 2 (OTf) 2 was generated in extending to the acetylation of disaccharide-derived polyols ( Scheme 1). 22 equiv. of acetic anhydride were used per hydroxy group. Pd(PhCN) (OTf) 2 was generated in by With these exciting results, substrate scope of Pd(PhCN) 2(OTf) 2 was further evaluated by With these exciting the substrate scope of Pd(PhCN) 2(OTf) 2 2was further evaluated 2results, Cl 2 (1the equiv.) and AgOTf (2 equiv.) in CH 2Cl 2 (1.25M). Isolated yield. situ from Pd(PhCN) extending it to the acetylation of disaccharide-derived polyols ( Scheme 1). a 2 equiv. b Pd(PhCN) c Isolated of acetic anhydride were used per hydroxy 2(OTf) 2 cwas2yield. generated in in in a 2 equiv. b Pd(PhCN) a 2 from b(CH 2Clanhydride 2 (12Cl equiv.) and AgOTf (2 equiv.) in polyols CH 2Cl 22(1.25M). situ Pd(PhCN) of acetic were used per hydroxy group. 2further (OTf) was generated 2 (1 equiv.) and AgOTf equiv.) in 2 (1.25M). yield. situ from Pd(PhCN) equiv. of anhydride were used per hydroxy group. Pd(PhCN) 2(OTf) 2 Isolated was generated extending it to the acetylation of disaccharide-derived polyols Scheme 1). extending it toacetic the acetylation of disaccharide-derived (2Cl Scheme 1). With these exciting results, the substrate scope of(2group. Pd(PhCN) (OTf) 2 was evaluated by WithPd(PhCN) these exciting results, the substrate scope of 2Pd(PhCN) 2(OTf) was further evaluated by c Isolated 2Cl2 (12Cl equiv.) and AgOTf (2 (2 equiv.) in in CH 2 (1.25M). yield. situ from c2 Isolated c Isolated 2equiv.) (1 equiv.) and AgOTf (2polyols equiv.) in CH Cl2 (1.25M). yield. situ from Pd(PhCN) 2Cl2 of (1 and AgOTf equiv.) CH 2Cl22(1.25M). yield. situ from extending it to thePd(PhCN) acetylation disaccharide-derived ( Cl Scheme 1).2(OTf) With these exciting results, the scope of Pd(PhCN) 2((OTf) 2 was evaluated by by With exciting results, the substrate scope of Pd(PhCN) 2 further was further evaluated extending itthese to the acetylation of substrate disaccharide-derived polyols Scheme 1). With these exciting results, the substrate scope of Pd(PhCN) 2 (OTf) 2 was further evaluated by extending itthese tothese the of disaccharide-derived polyols ( Scheme 1).2 was With exciting results, substrate scope of polyols Pd(PhCN) 2(OTf) 21). was further evaluated extending it exciting toacetylation the acetylation ofthe disaccharide-derived Scheme With results, the substrate scope of Pd(PhCN) 2((OTf) further evaluated by by extending it it toto the ofof disaccharide-derived polyols ( Scheme 1).1). 1). extending it the toacetylation the acetylation of disaccharide-derived polyols ( Scheme extending acetylation disaccharide-derived polyols ( Scheme
Catalysts 2016, 6, 27 Catalysts2016, 2016,6,6,27 27 Catalysts
7 of 10 of10 10 77of
OAc OAc OH OH HO HO HO HO
OH OH OH OOOH
OO HOOO HO
Ac22OO Ac
++ OH OH
mol% 11mol% AcO AcO AcO Pd(PhCN)22(OTf) (OTf)22 AcO Pd(PhCN) rt, 1h, 1h,85% Cl22, ,rt, CH22Cl 85% CH
OO
OAc OAc
OAc OAc
OH OH
HOOO HO HO HO Maltose Maltose
AcOOO AcO OAc 23 OAc 23
Sucrose OH Sucrose OH OH OH HO HO HO HO
OAc OAc OAc OOOAc
OO
OO
++
Ac22OO Ac
OH OH
mol% 11mol% Pd(PhCN)22(OTf) (OTf)22 Pd(PhCN)
AcO AcO AcO AcO
CH22Cl Cl22, ,rt, rt, 45min, 45min, 79% CH 79%
OH OH
OH HO OH HO OO OH OH HO HO HOOO HO OO OH OH HO HO OH OH Lactose Lactose
++
Ac22OO Ac
mol% 11mol% (OTf)22 Pd(PhCN)22(OTf) Pd(PhCN) CH22Cl Cl22, ,rt, rt, 30min, 30min,93% CH 93%
OO
OAc OAc
AcOOO AcO AcO AcO 24 24
OO
OAc OAc OAc OAc
OAc AcO OAc AcO OO OAc OAc AcO AcO AcOOO AcO OO OAc OAc AcO AcO OAc OAc 25 25
Scheme 1. Pd(PhCN)2 (OTf)2 catalyzed acetylation of disaccharide-derived polyols. Scheme1.1.Pd(PhCN) Pd(PhCN)22(OTf) (OTf)22catalyzed catalyzedacetylation acetylationof ofdisaccharide-derived disaccharide-derivedpolyols. polyols. Scheme
Using sucrose, maltose and lactose as starting materials, the corresponding acetylated Usingsucrose, sucrose,maltose maltoseand andlactose lactoseas asstarting startingmaterials, materials,the thecorresponding correspondingacetylated acetylateddisaccharides disaccharides Using disaccharides 23, 24 and 25 were isolated in good to excellent yields using only 1 mol% catalyst loading. 23,24 24and and25 25were wereisolated isolatedin ingood goodto toexcellent excellentyields yieldsusing usingonly only11mol% mol%catalyst catalystloading. loading. 23, With these excellent conversions and catalyst turnover, we proceeded to explore the origin of the With these these excellent excellent conversions conversions and and catalyst catalyst turnover, turnover, we we proceeded proceeded to to explore explore the the origin origin of of With observed catalytic activity by conducting a number of control experiments using benzyl alcohol as the the observed observed catalytic catalytic activity activity by by conducting conducting aa number number of of control control experiments experiments using using benzyl benzyl alcohol alcohol the model substrate (Table 5). asthe themodel modelsubstrate substrate(Table (Table5). 5). as Table A control experiment Table5. Acontrol controlexperiment experimentwith withbenzyl benzylalcohol alcoholas assubstrate. substrate. Table 5.5.A with benzyl alcohol as substrate.
Entry
Entry Entry 11 22 33
Catalyst
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1 No catalyst Catalyst Catalyst 2 Pd(PhCN)2 Cl2 3 No AgOTf Nocatalyst catalyst 4 Pd(PhCN)2 (OTf)2 a a 5 Pd(PhCN) Pd(PhCN) Pd(PhCN) Cl22(OTf) 2 22Cl 2 6 TfOH AgOTf 2 (OTf)2 a AgOTf 7 Pd(PhCN) Pd(CH3 CN)4 (OTf)2 8
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2
55
2
c
DTBP = 2,6-Di-tert-butylpyridine. Isolated yield.
(OTf)22aa Pd(PhCN)22(OTf) Pd(PhCN)
Additive Additive
1 mol% 2--mol% 1 mol% 1 mol% mol% 11mol% 2 mol% mol% 22mol% 1 mol% 1 mol%
(OTf) mol% Pd(PhCN) 22(OTf) 22aa 11mol% 44 a Pd(PhCN) Pd(PhCN) (OTf) was generated in situ from Pd(PhCN) b
Additive
mol% 11mol%
- -DTBP--b Hg(0)--
2 Cl2
-
Time
Yield (%) c
5 h Time Time < 1 Yield Yield(%) (%)cc 5h
